We are searching for genes involved in neurologic and psychiatric disorders, with a particular emphasis on bipolar affective disorder and schizophrenia. The clinical heterogeneity seen within these inherited disorders is likely due to environmental influences as well as mutations in genes (multifactorial). Molecular techniques are used to identify mutations that may be predictive of different patient presentations and to understand the molecular mechanisms leading to nervous system abnormalities. We have isolated and characterized genes, such as the neurotransmitter biosynthetic enzymes human tyrosine hydroxylase and tryptophan hydroxylase, that may be involved in neuropsychiatric disorders. Using restriction length fragment polymorphisms (RFLP) and microsatellite DNA markers, we are genotyping DNA from individuals in large families where there is a high risk for affective disorder and we are performing linkage analysis in order to identify chromosome regions harboring susceptibility or protective genes involved in bipolar affective disorder (see Project #Z01 MH 02625-08 NS). For the chromosome regions that are identified expressed sequences will be isolated and characterized. Human genomic DNA containing trinucleotide repeats is being isolated and characterized. We have found a trinucleotide repeat on chromosome 17q that accounts for most expansions detected by the Repeat-Expansion Detection (RED) technique. Cytogenetic studies, including fluorescent in-situ hybridization (FISH), on cells from individuals affected with bipolar affective disorder, schizophrenia (particularly childhood onset, see Project #MH-02581-08 CHP), mental retardation, autism, and attention deficit hyperactivity disorder (ADHD), are being performed to identify chromosomal abnormalities that may aid in the identification of disease genes. We have identified chromosome 22q11.2 interstitial deletions among childhood onset schizophrenics, and also the association of an X-chromosome dodecamer insertional variant allele with mental retardation. The results of this research should provide a molecular basis for diagnosis and for the development of novel therapeutic strategies for these disorders.